Type-2 diabetes is a metabolic disorder that affects >150 million individuals worldwide and represents the sixth highest cause of death in the U.S. in 2002. Heart disease and stroke account for about 65 percent of deaths in people with diabetes and adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes. These observations underline the devastating effects of diabetes and the urgency of providing the clinicians and the pharmaceutical industry with novel targets and clinical tools, such as specific small molecule drugs for the development of novel therapies. It is now clear that activation of the protein kinase JNK could act as an important negative feedback regulator of insulin signaling. JNK is regulated by JNK-interacting protein-1, JIP1, a scaffolding protein which enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. The JNK-JIP1 interaction is mediated by a specific peptide region on JIP1 (pepJIPI). Recent in vivo data with a cell-permeable JIP1 peptide showed that its administration in both genetically and dietary mice models of insulin resistance and type-2 diabetes restored normoglycemia without causing hypoglycemia in lean mice. Numerous laboratories around the world are using this peptide to probe the involvement of the JNK pathway in diabetes and other human disorders. We propose a highly integrated, multidisciplinary approach to derive novel, safe and efficacious drug-like JIP mimics and to test the most promising compounds in mice models of diabetes. The most promising and validated compounds will be deposited in the NIH chemical repository and made available as a resource to the entire scientific community. Relevance: Overall, the risk for death among people with diabetes is about twice that of people without diabetes of similar age, with heart disease and stroke accounting for about two thirds of deaths in people with diabetes. In addition, diabetes is the leading cause of new cases of blindness among adults aged 20 to 74 years, as well as kidney failure, accounting for 44 percent of new cases in 2002. Central to insulin regulation, the interactions between the protein kinase JNK and the scaffolding protein JIP1 activate a series of cellular events which result in altered insulin signaling. A central hypothesis in this study is that the development of compounds capable of interfering with the JNK-JIP1 interactions (JIP mimics) represents a promising, innovative, yet unexplored route to advance novel therapies against diabetes.